1. Field of the Invention
The present invention relates to new substituted thieno(2,3b)pyrazine derivatives, and salts or prodrugs thereof, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular to their use, either alone or in combination with at least one additional therapeutic agents, for the manufacture of a medicament in the prophylaxis or treatment of cancer.
2. Description of Related Art
Cellular growth, proliferation and differentiation are known to be regulated by receptor protein kinases. Via key signal transduction cascades many physiological functions are being controlled. In cancer cells, activation of signal transduction cascades results in tumor formation and growth, progression of the disease and metastasis of the tumor. The Ras/Raf/MEK/ERK pathway is one of the most important pathways in the regulation of cell growth and proliferation (Reviewed in e.g.: Wellbrock et al, Nat. Rev. Mol. Cell. Biol 2004; Kinkade et al, Curr. Canc. Ther. Rev. 2006, Michaloglou et al, Oncogene 2008). Signal transduction in this pathway starts with the activation of Ras (eg by growth factors). Upon activation of Ras, Raf is recruited to the plasma membrane and is phosphorylated and activated. Activated Raf in turn then phosphorylates and activates MEK, which in turn phosphorylates and activates ERK. Phosphorylated ERK then translocates to the nucleus and activates several downstream transcription factors.
Three Raf serine/threonine protein kinase isoforms have been reported, Raf-1 (C-Raf), A-Raf and B-Raf. These Raf kinases are highly homologous but have distinct biochemical functions, including differences in activation of the kinase pathways and tissue distribution. The basal kinase activity of B-Raf is considerably higher then of A-Raf and C-Raf (Chong et al, Cell Signal 2003).
Activation of the Ras/Raf/MEK/ERK pathway has been shown to stimulate cell cycle progression and is found in many tumors. Activating Ras mutations are found in several cancers (15% of human tumors have a Ras mutation), including pancreatic and colorectal tumors. B-Raf mutations are frequently found in melanomas (45-68% of melanomas have a B-Raf mutation), thyroid tumors (10-54%), ovarian tumors (31-36%) and colorectal tumors (9%) (Davies et al, Nature 2002; Khazak et al, Expert Opin. Ther. Targets 2007).
The most frequent mutation in B-Raf is a replacement of a valine at position 600 in a glutamic acid. The presence of a Glu600 in the mutated form obviates the need for phosphorylation, resulting in uncoupling of the Ras/Raf/MEK/ERK activating pathway and in constitutively active B-Raf (Wan et al, Cell 2004, Gray-Schopfer et al, Nature 2007).
In the Ras/Raf/MEK/ERK pathway, the Raf protein kinases play a central role and have been shown to be critical for mediating cell proliferation in various cancer models. Therefore it can be expected that B-Raf inhibitors are of therapeutic use in the treatment of tumors which are dependent on this pathway as a single agent therapy. Moreover, administration of a Raf inhibitor in combination with a chemotherapeutic agent (such as temozolomide or paclitaxel/docetaxel) can be of benefit for patients with tumors dependent on the Ras/Raf/MEK/ERK pathway. Furthermore, it has been reported that in melanomas both the Ras/Raf/MEK/ERK pathway as well as the PI3K/Akt/mTor pathway are drivers of tumor growth and progression. Intervention of both pathways by the combined treatment of a Raf inhibitor and an inhibitor of the PI3K pathway could be a valuable therapy (Smalley et al, Brit. J. Canc. 2009).
Quinoxalines as B-Raf inhibitors are disclosed in AstraZeneca application WO 06040568. Quinoazolinone derivatives are disclosed as B-Raf inhibitors in application WO 06024834 (WO 06024836). Quinazoline carboxamides and thiazole carboxamides are described in international application WO 08157575 and WO 06081172.